The genus Phlebovirus is one of five genera of the Bunyaviridae family. Phleboviruses are enveloped spherical viruses with icosahedral symmetry. The genome of phleboviruses consists of three single-stranded RNA genome segments—small (S), medium (M) and large (L). The M and L segments use a negative sense coding strategy, while the S segment encodes two proteins using an ambisense strategy. The S segment encodes the non-structural protein NSs in the positive sense orientation and the nucleocapsid (N) protein in the negative sense orientation; each protein is translated from a subgenomic virus mRNA. The M segment encodes the glycoprotein precursor that is cleaved by host proteases into two structural domains—Gn and Gc. The L segment encodes the L protein, which functions as the RNA-dependent RNA polymerase in primary and secondary transcription to generate mRNA and replicative intermediates, respectively.
Heartland virus (HRTV) is a newly identified member of the Phlebovirus genus. It was first isolated from leukocytes of two Missouri farmers in separate incidences hospitalized in 2009 (McMullan et al., N Engl J Med 367: 834-841, 2012; PCT Publication No. WO 2013/142808). Each subject experienced similar, though not identical symptoms of fever, headache, anorexia, gastrointestinal distress and fatigue, and both reported recent tick bites. Initial investigations for erhlichiosis and rickettsial diseases returned negative results, and EDTA-treated blood taken two days after hospital admission was taken for further investigation (McMullan et al., N Engl J Med 367: 834-841, 2012). After cytopathic effect without bacterial microcolonies was observed in cell culture approximately nine days post-inoculation, a viral infection was suspected. Thin-section electron microscopy revealed enveloped particles consistent in size with those of the Bunyaviridae family Next-generation sequencing and phylogenetic analysis confirmed the discovery of isolates of a novel bunyavirus of the genus Phlebovirus, which was subsequently named Heartland virus.
HRTV is believed to be transmitted to humans by the bite of an infected Amblyomma americanum tick (Savage et al., Am J Trop Med Hyg 89: 445-452, 2013). It causes severe disease characterized by fever, leukopenia and thrombocytopenia (McMullan et al., N Engl J Med 367: 834-841, 2012). HRTV is closely related to severe fever with thrombocytopenia virus (SFTSV), a phlebovirus causing severe disease in China and neighboring countries (Yu et al., N Engl J Med 364: 1523-1532, 2011.). SFTSV is also thought to be transmitted by ticks. The average case fatality rate of SFTSV infection is between 6-17% with the most severe manifestations occurring in elderly individuals (Xu et al., PLoS Pathog 7: e1002369, 2011).